KR100342600B1 - New Thiazole compounds and their preparations - Google Patents
New Thiazole compounds and their preparations Download PDFInfo
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- KR100342600B1 KR100342600B1 KR1020000011127A KR20000011127A KR100342600B1 KR 100342600 B1 KR100342600 B1 KR 100342600B1 KR 1020000011127 A KR1020000011127 A KR 1020000011127A KR 20000011127 A KR20000011127 A KR 20000011127A KR 100342600 B1 KR100342600 B1 KR 100342600B1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/40—Unsubstituted amino or imino radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D277/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
본 발명은 세펨계 항생제 세프타지딤, 세픽심을 비롯하여 아래 구조식의 중간체를 함유하는 세파계 항생제 제조에 매우 유용하게 사용될 수 있는 다음 구조식(I)로 표시되는 신규한 결정성 아미노 티아졸 유도체 및 이의 제조 방법에 관한 것이다.The present invention relates to a novel crystalline aminothiazole derivative represented by the following structural formula (I) which can be very usefully used for the production of ceftazidime antibiotic ceftazidime, ≪ / RTI >
상기 구조식에서, R1및 R2는 동일하거나 다를 수도 있으며 H, C1~C4의 알킬기, C3~C5의 사이클로 알킬기 등을, X는 염소, 브롬, 산부가염의 산은 무기산(염산, 브롬산, 황산, 과염소산 등), 유기산(포름산, 초산, 삼불화초산, 프로피온산, 메탄 술폰산, 벤젠술폰산 등)을 의미한다.In the above formulas, R 1 and R 2 may be the same or different and are H, a C 1 -C 4 alkyl group, a C 3 -C 5 cycloalkyl group, and the like, X is an acid of chlorine, bromine, Bromic acid, sulfuric acid, perchloric acid, etc.), and organic acids (formic acid, acetic acid, trifluoroacetic acid, propionic acid, methanesulfonic acid, benzenesulfonic acid and the like).
Description
본 발명은 세펨계 항생제 세프타지딤, 세픽심을 비롯하여 아래 구조식의 중간체를 함유하는 세파계 항생제 제조에 매우 유용하게 사용될 수 있는 다음 구조식(I)로 표시되는 신규한 결정성 아미노 티아졸 유도체 및 이의 제조 방법에 관한 것이다.The present invention relates to a novel crystalline aminothiazole derivative represented by the following structural formula (I) which can be very usefully used for the production of ceftazidime antibiotic ceftazidime, ≪ / RTI >
상기 구조식에서,In the above formula,
R1및 R2는 동일하거나 다를 수도 있으며 H, C1~C4의 알킬기, C3~C5의 사이클로 알킬기 등을, X는 염소, 브롬, 산부가염의 산은 무기산(염산, 브롬산, 황산, 과염소산 등), 유기산(포름산, 초산, 삼불화초산, 프로피온산, 메탄 술폰산, 벤젠술폰산 등)을 의미한다.R 1 and R 2 may be the same or different and are H, a C 1 -C 4 alkyl group, a C 3 -C 5 cycloalkyl group, and the like, X is an acid of chlorine, bromine or an acid addition salt with inorganic acids such as hydrochloric acid, , Perchloric acid, etc.), and organic acids (formic acid, acetic acid, trifluoroacetic acid, propionic acid, methanesulfonic acid, benzenesulfonic acid and the like).
세팔로스포린계 항생제 제조방법에 대한 선행 기술은 문헌이나 특허에 무수히 많이 보고되었으며, 이러한 선행 기술은 공통적으로 3-세펨 화합물의 아미노기와 아실화 반응을 시킴에 있어 다음 구조식 (I-1)로 표시되는 2-아미노티아졸 카르복실산 화합물을 반응성 유도체로 전환시킨 다음 아실화 반응시킴으로써 세펨화합물을 제조하고 있다.The prior art for the preparation of cephalosporin antibiotics has been reported in numerous literatures and patents, and these prior arts are commonly referred to as the following structural formula (I-1) for the acylation reaction of amino groups of 3-cephem compounds Aminothiazole carboxylic acid compound is converted into a reactive derivative and then acylation reaction is carried out to prepare a cephem compound.
상기 구조식에서,In the above formula,
R1, R2는 전술된 바와 같고, R3는 통상적으로 사용되어지는 카르복시 보호기, Ra는 수소 또는 아미노 보호기이다.R 1 and R 2 are as defined above, R 3 is a commonly used carboxy protecting group, and R a is hydrogen or an amino protecting group.
이때, 상기 구조식(I-1)의 반응성 유도체로는 산할로겐화물, 반응성 에스테르, 반응성 아마이드 또는 혼합산 무수물 등을 예로 들 수 있다. 그러나, 이러한 반응성 유도체들이 산할로겐화물인 경우에는 까다로운 반응 조건하에서 제조될 뿐만 아니라 통상적으로 티아졸의 아미노기를 먼저 보호시키고 산할로겐화제를 사용하여 반응성 산할로겐화물로 전환시킨 후 분리되지 않은 채 그대로 아실화 반응에 이용됨으로써 아실화제와의 원하지 않는 부반응이 진행되어 부산물이 생성되는 등의 문제점이 있으며 특히 각각의 관능기를 보호한 상태에서의 반응이므로 결과적으로 얻은 축합산물의 보호기를 각각 제거하여야 되는 번거로움이 있다.The reactive derivative of the structural formula (I-1) may be an acid halide, a reactive ester, a reactive amide or a mixed acid anhydride. However, when these reactive derivatives are acid halides, they are not only prepared under difficult reaction conditions but also usually the amino groups of the thiazoles are first protected and converted to the reactive acid halides using acid halogenating agents, There is a problem in that undesired side reaction with the acylating agent proceeds and by-products are produced by the use in the miscibility reaction. In particular, since the reaction is in a state in which each functional group is protected, the resulting protecting group of the condensation product must be removed .
또한, 상기 구조식(I-1) 화합물의 반응성 에스테르나 반응성 아마이드를 이용 아실화 반응시 수율이 저조할 뿐만 아니라, 이들 반응성 유도체의 반응성도 낮아서 아실화시 반응 시간이 길고 더욱이 반응 후 생성되는 부산물들의 제거가 용이치 않아 아실화 반응 후 고수율, 고순도의 축합산물을 얻기가 어렵다는 문제점이 있다.In addition, not only the yields of the acylation reaction using the reactive ester or the reactive amide of the compound of the structural formula (I-1) are low, but also the reactivity of these reactive derivatives is low, so that the reaction time during acylation is long, There is a problem that it is difficult to obtain a high yield and high purity condensation product after the acylation reaction.
이에 본 발명자들은 상기한 종래 방법의 문제점을 해결하고자 새로운 방법에 대한 연구를 거듭한 결과 지금까지 알려진 바가 없는 상기 구조식(I)의 새로운 중간체를 개발하였고, 이 신규 화합물은 3-세펨 화합물의 아미노기와 아실화 반응 전에 각각의 보호기가 제거된 순수한 결정형 형태의 산할로겐화물로 얻어지므로 이를이용하여 세프타지딤, 세픽심 등을 제조하여 본 결과 반응 시간도 짧을 뿐만 아니라 아실화 반응 후 부산물들이 거의 없어 고수율, 고순도의 목적화합물을 제조할 수 있게 되어 본 발명을 완성하게 되었다. 따라서, 본 발명은 세프타지딤, 세픽심 등의 제조에 유용하게 사용될 수 있는 다음 구조식(I)로 표시되는 신규한 아미노티아졸 화합물 및 그의 제조방법을 제공하는 데 그 목적이 있다.As a result, the inventors of the present invention have developed new intermediates of the above formula (I) which have not been known until now, As a result, the reaction time is short as well as the byproducts after the acylation reaction and there is almost no by-products after the acylation reaction. Yields and high purity of the desired compound, thereby completing the present invention. Accordingly, it is an object of the present invention to provide a novel aminothiazole compound represented by the following structural formula (I) which can be usefully used for the production of ceftazidime, septicem, etc., and a process for producing the same.
상기식에서,In this formula,
R1, R2및 X는 전술한 바와 같다.R 1 , R 2 and X are as described above.
도 1은 본 발명에 따른 (Z)-2-(2-카르복시프로프-2-옥시이미노)-2-(2-아미노티아졸-4-일)아세틸클로라이드 일염산염의 데바이-쉐러 X-선 분말 회절 스펙트럼을 나타낸 것이다.Figure 1 is a schematic diagram of a DeBa-Scherrer X-ray spectrum of (Z) -2- (2-carboxyprop-2-oxyimino) -2- (2-aminothiazol- Powder diffraction spectrum.
도 2는 본 발명에 따른 (Z)-2-(2-카르복시메톡시이미노)-2-(2-아미노티아졸-4-일)아세틸클로라이드 일염산염의 데바이-쉐러 X-선 분말 회절 스팩트럼을 나타낸 것이다.Figure 2 shows the Devai-Scherrer X-ray powder diffraction spectrum of (Z) -2- (2-carboxymethoxyimino) -2- (2-aminothiazol-4-yl) acetyl chloride monohydrochloride according to the invention .
이하, 본 발명을 더욱 상세히 설명하면 다음과 같다.Hereinafter, the present invention will be described in more detail.
본 발명의 목적화합물인 일반식(I)의 신규 아미노 티아졸 유도체를 제조하는 방법을 간략히 도식하면 아래와 같다.The method for producing the novel aminothiazole derivative of the general formula (I), which is the object compound of the present invention, is briefly described as follows.
상기 구조식(I)의 신규 아미노 티아졸 유도체를 제조함에 있어서, 상기 구조식(II)의 유기산은 일반 시약인 에틸 2-아미노-α-(히드록시이미노)-4-티아졸 아세테이트를 출발물질로 하여 통상적인 화학지식을 응용하여 합성할 수 있다.In the preparation of the novel aminothiazole derivatives of formula (I), the organic acid of formula (II) can be prepared by reacting ethyl 2-amino-? - (hydroxyimino) -4-thiazole acetate, It can be synthesized by applying a common chemical knowledge.
출발물질(II)을 이용하여 상기 구조식(II-1)의 산할로겐화물을 거쳐 목적 화합물(I)을 제조함에 있어 먼저 카르복시기를 포스포러스 펜타클로라이드, 포스포러스 트리클로라이드 등의 산할로겐화제를 이용하여 산 염화물로 만들고 -바람직하게는 포스포러스옥시트리클로라이드 사용-분리 과정 없이 반응액상에서 무기산 또는 유기산을 사용 카르복시 보호기를 제거함과 동시에 산부가염의 형태로 결정화시켜 여과하여 불필요한 부산물을 제거하고 순수하고 안정한 형태의 결정성목적화합물(I)을 이용하여 7-아미노세팔로스포린 유도체를 도입하면 아실화 반응 후 카르복실기 보호기의 제거 과정이 불필요하게 되어 보다 더 경제적으로 세팔로스포린 유도체를 제조할 수 있을 뿐만 아니라 고순도의 세팔로스포린 유도체를 제조할 수 있다.In the preparation of the desired compound (I) via the acid halide of the above structural formula (II-1) using the starting material (II), the carboxyl group is first reacted with an acid halide such as phosphorus pentachloride or phosphorus trichloride Acid chloride - preferably phosphorus oxytrichloride - eliminates the carboxy protecting group by using inorganic acid or organic acid in the reaction liquid without separation process, crystallizes in the form of acid addition salt and filtrates to remove unnecessary by-products, The amorphous cephalosporin derivative can be produced more economically by introducing the 7-amino cephalosporin derivative by using the target compound (I), since the process of removing the carboxyl group protecting group after the acylation reaction becomes unnecessary, Can be prepared.
본 발명에서 일반식(II-1)의 화합물을 제조하기 위해 사용되는 용매로는 메틸렌클로라이드, 클로로포름, 디에틸에테르, 아세토니트릴, 1,2-디클로로에탄, 아세톤 등이 포함되며 이중 메틸렌클로라이드 단독이거나 메틸렌클로라이드, 디에틸에테르 혼합 용매의 사용이 가장 바람직하다. 반응은 통상적으로 -20℃~30℃의 온도에서 수행되나 가장 바람직하게는 0℃~5℃에서 수행하는 것이 좋다.In the present invention, the solvent used for preparing the compound of formula (II-1) includes methylene chloride, chloroform, diethyl ether, acetonitrile, 1,2-dichloroethane, acetone, etc., Most preferred is the use of a mixed solvent of methylene chloride and diethyl ether. The reaction is usually carried out at a temperature of -20 ° C to 30 ° C, but most preferably at 0 ° C to 5 ° C.
일반식(II)에서 일반식(II-1)의 산할로겐화물을 만들기 위해 사용할 수 있는 할로겐화제는 포스포러스펜타클로라이드, 포스포러스트리클로라이드, 포스포러스옥시클로라이드, 티오닐클로라이드, 옥살릴클로라이드, 포스포러스트리브로마이드, 설퍼릴클로라이드 등을 사용할 수 있으나 가장 바람직하게는 포스포러스옥시클로라이드를 사용함이 가장 바람직하다.Halogenating agents which can be used to make the acid halides of formula (II-1) in the general formula (II) are phosphorus pentachloride, phosphorus trichloride, phosphorus oxychloride, thionyl chloride, oxalyl chloride, Sulfuric acid, sulfuric acid, sulfuric acid, sulfuric acid, sulfuric acid, sulfuric acid, sulfuric acid, sulfuric acid, sulfuric acid, sulfuric acid, sulfuric acid,
액상에서 일반식(II-1)의 산할로겐화물을 거쳐 일반식(I)의 산할로겐화물.산부가염을 제조하기 위해 사용되는 용매로는 상기 일반식(II-1) 제조시의 용매와 같이 메틸렌클로라이드, 클로로포름, 디에틸에테르, 아세토니트릴, 1,2-디클로로에탄 등이 포함되며 에테르류 및 할로저급 알칸류의 용매와의 혼합용매가 바람직하게 사용되어질 수 있다.The acid halide of general formula (I) via the acid halide of general formula (II-1) in liquid phase . Examples of the solvent used for preparing the acid addition salt include methylene chloride, chloroform, diethyl ether, acetonitrile, 1,2-dichloroethane and the like as a solvent in the production of the compound represented by the formula (II-1) A mixed solvent with a solvent of a halo-lower alkane may preferably be used.
또한, 일반식(II-1)의 카르복시보호기 제거와 동시에 결정형 산부가염 형태를 만들기 위해 사용되어지는 적당한 산으로는 무수염산, 무수브롬산, 무수요오드산, 과염소산, 디에틸에테르에 희석된 염산, 초산에 희석된 염산, 초산에 희석된 브롬산, 황산 등의 무기산과 포름산, 초산, 삼불화초산, 프로피온산, 메탄술폰산, 벤젠술폰산, p-톨루엔술폰산 등이 있다.Suitable acids which may be used to form the crystalline form of the acid salt form of the compound of formula (II-1) at the same time as the carboxy protecting group is removed include anhydrous hydrochloric acid, anhydrous bromic acid, anhydrous iodic acid, perchloric acid, Acetic acid, trifluoroacetic acid, propionic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like, with hydrochloric acid diluted with acetic acid, bromic acid diluted with acetic acid, sulfuric acid and the like and formic acid, acetic acid, trifluoroacetic acid,
이러한 가수분해에 적당한 산은 제거해야 할 보호기의 종류에 따라 선택할 수도 있으며 경우에 따라 mp-크레졸, 페놀, 아니솔 등 양이온 포착제의 존재하에서 반응을 수행할 수도 있다 반응 온도는 산할로겐화 제조시와 비슷하게 -20℃~30℃의 온도에서 수행되나 가장 바람직하게는 -5℃~10℃에서 수행하는 것이 좋다.The acid suitable for this hydrolysis may be selected depending on the type of protecting group to be removed and, in some cases, the reaction may be carried out in the presence of a cation scavenger such as mp-cresol, phenol or anisole. It is preferably carried out at a temperature of -20 ° C to 30 ° C, but most preferably at -5 ° C to 10 ° C.
일반식(I)의 화합물은 상기 반응액을 증류, 농축 과정 없이 카르복시기의 탈보호가 된 후 반응액 내에서 산부가염의 형태로 자연스럽게 석출되어 용이하게 분리, 수득할 수 있는 결정성 화합물이다. 이는 X-선 회절 분석을 통하여 그 결정성이 입증되었으며 이 스펙트럼은 도 1, 도 2에 나타난 바와 같다. 도 1, 도 2의 X-선 분말 회절 스펙트럼에서 이의 특징적인 피이크가 잘 나타나 있으며 다음의 표 1, 표 2에 상기 구조식(I)의 결정성 화합물의 고유한 데바이-쉐러(Debay-scherrer) X-선 분말 회절 패턴을 나타내었다. 여기서 '2θ'는 회절각을 'd'는 결정면간의 거리를 'I/I0'는 상대적 세기를 나타낸다.The compound of the general formula (I) is a crystalline compound which can be easily separated and obtained by naturally precipitating the reaction solution in the form of an acid addition salt after deprotection of the carboxyl group without distillation and concentration process. This was confirmed by X-ray diffraction analysis and its spectrum is as shown in FIG. 1 and FIG. The distinctive peaks of the X-ray powder diffraction spectra of FIGS. 1 and 2 are well illustrated and the following Debye-Scherrer X - line powder diffraction pattern. Here, '2θ' is the diffraction angle, 'd' is the distance between the crystal planes, and 'I / I 0 ' is the relative intensity.
이하, 본 발명을 실시예에 의거하여 구체적으로 설명하면 다음과 같으며 본 발명이 이에 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.
실시예 1 .(Z)-2-(2-카르복시프로프-2-옥시이미노)-2-(2-아미노티아졸-4-일)아세틸클로라이드 일염산염의 제조Example 1 Preparation of (Z) -2- (2-carboxyprop-2-oxyimino) -2- (2-aminothiazol-4-yl) acetyl chloride monohydrochloride
디클로로메탄 2000mL 및 디에틸에테르 2000mL 혼합액을 0℃~5℃까지 냉각시킨 후 포스포러스옥시클로라이드 55mL와 N,N-디메틸포름아마이드 38mL를 차례로 적가하고 동온도에서 30분간 교반하여 준 후 (Z)-2-(2-t-부톡시카르보닐프로프-2-옥시이미노)-2-(2-아미노티아졸-4-일)아세트산 100g을 가하고 1시간 동안 교반시킨다. 반응액을 -15℃~-20℃까지 냉각시킨 후 무수 염산을 1시간 동안 500mL~1L/분당의 속도로 주입시킨 후 1시간 동안 교반하면 카르복시기의 탈보호 반응이 진행됨과 동시에 결정이 석출되기 시작한다. 이때 결정화된 고체를 여과하여 디메틸클로라이드, 디에틸에테르 각 100mL씩 세척한 후 진공 건조시켜 백색 고체인 표제화합물 85g(수율 86%) 얻었다.After cooling the mixture to 2000 mL of dichloromethane and 2000 mL of diethyl ether, the mixture was cooled to 0 ° C to 5 ° C, and then 55 mL of phosphorus oxychloride and 38 mL of N, N-dimethylformamide were added dropwise in that order. The mixture was stirred at the same temperature for 30 minutes, 100 g of 2- (2-t-butoxycarbonylprop-2-oxyimino) -2- (2-aminothiazol-4-yl) acetic acid was added and stirred for 1 hour. After the reaction solution was cooled to -15 ° C to -20 ° C, anhydrous hydrochloric acid was fed at a rate of 500mL to 1L / min for 1 hour, and then stirred for 1 hour to carry out the deprotection reaction of the carboxyl group and precipitate crystals do. At this time, the crystallized solid was filtered, washed with 100 mL each of dimethyl chloride and diethyl ether, and then vacuum-dried to obtain 85 g (yield 86%) of the title compound as a white solid.
융점(℃) : 153~158 (분해)Melting point (캜): 153 to 158 (decomposition)
1NMR : (δ, DMSO-d6) ; 1.51(s, 6H), 7.19(s, 1H) 1 NMR: (δ, DMSO- d 6); 1.51 (s, 6 H), 7.19 (s, 1 H)
실시예 2. (Z)-2-(2-카르복시메톡시이미노)-2-(2-아미노티아졸-4-일)아세틸클로라이드 일염산염의 제조Example 2 Preparation of (Z) -2- (2-carboxymethoxyimino) -2- (2-aminothiazol-4-yl) acetyl chloride monohydrochloride
디클로로메탄 500mL에 포스포러스펜타클로라이드 65g을 가하고 10분간 교반시킨 후 (Z)-2-(2-t-부톡시카르보닐메톡시이미노)-2-(2-아미노티아졸-4-일)아세트산 100g을 가하여 0℃~5℃의 온도 범위에서1시간 동안 교반한다. 이 반응액에 70% 과염소산 30ml를 적가하여 30분 정도 교반시킨 후 디에틸에테르 100mL, mp-크레졸 100mL를 가한다. 1시간 교반 후 생성된 결정을 여과하고 디에틸에테르 100mL와 디클로로메탄 100mL씩 차례로 세척하여 준 후 실온에서 밤새 진공 건조하여 백색 고체 화합물 85g(수율 86%) 얻었다.65 g of phosphorus pentachloride was added to 500 mL of dichloromethane and the mixture was stirred for 10 minutes. Then, a solution of (Z) -2- (2-t-butoxycarbonylmethoxyimino) -2- (2-aminothiazol- And the mixture is stirred for 1 hour in a temperature range of 0 ° C to 5 ° C. To this reaction mixture, 30 ml of 70% perchloric acid is added dropwise and the mixture is stirred for about 30 minutes. Then, 100 ml of diethyl ether and 100 ml of mp-cresol are added. After stirring for 1 hour, the resulting crystals were filtered, washed with 100 ml of diethyl ether and 100 ml of dichloromethane in this order, and then vacuum-dried at room temperature overnight to obtain 85 g of a white solid compound (yield 86%).
융점(℃) : 132~134 (분해)Melting point (占 폚): 132 to 134 (decomposition)
1NMR : (δ, DMSO-d6) ; 4.68(s, 2H), 7.07(s, 1H) 1 NMR: (δ, DMSO- d 6); 4.68 (s, 2 H), 7.07 (s, 1 H)
본 발명의 결정성 아미노 티아졸 유도체의 산염화물을 이용하여 세프타지딤 오수화물을 제조하였다.Ceftazidime pentahydrate was prepared using the acid chloride of the crystalline aminothiazole derivative of the present invention.
제조예. 7-{2-(2-아미노티아졸-4-일)-2-(Z)-(2-카르복시프로프-2-옥시이미노)아세트아미도}-3-(1-피리디니움메틸)-세프-3-엠-4-카르복실레이트Production example. 2- (Z) - (2-carboxyprop-2-oxyimino) acetamido} -3- (1-pyridiniummethyl) - Ce-3-M-4-carboxylate .. 오수화물(세프타지딤Seaweed (ceftazidime 오수화물)의 제조Lt; / RTI >
디클로로메탄 100mL에 7-아미노-3-(1-피리디니움메틸)-세프-3-엠-4-카르복실레이트.하이드로요오다이드 10g을 가하고 트리에틸아민 4mL를 0~10℃의 온도 범위에서 적가하여 완전히 용해시킨다. 여기에 (Z)-(2-카르복시프로프-2-옥시이미노)-2-(2-아미노티아졸-4-일)-아세틸클로라이드.일염산염 9.4g을 30분간 3~4회 나누어 가하고 30분간 0~10℃의 온도에서 교반시킨다. 반응액에 물 50mL를 가하여 층분리하고 물층을 취하여 활성탄 2g을 가하여 30분간 다시 교반한다. 규조토를 이용 여과하여 활성탄을 제거하고 물층에 2N-염산 용액으로 pH 3.8로 조절한 다음 5℃에서 12시간 방치시킨다. 생성된 결정을 여과하고 빙수와 아세톤으로 순차적으로 세척하여 건조시키면 백색의 목적화합물 12.1g(수율 : 80%)를 얻었다.To 100 mL of dichloromethane was added 7-amino-3- (1-pyridiniummethyl) -cep-3-yl-4-carboxylate . 10 g of hydroiodide is added and 4 ml of triethylamine is added dropwise in the temperature range of 0 to 10 ° C to dissolve completely. (Z) - (2-carboxyprop-2-oxyimino) -2- (2-aminothiazol-4-yl) -acetyl chloride . 9.4 g of monohydrochloride is added in three to four divided portions for 30 minutes, and the mixture is stirred for 30 minutes at a temperature of 0 to 10 ° C. 50 ml of water was added to the reaction mixture to separate the layers, and 2 g of activated carbon was added to the water layer, followed by stirring again for 30 minutes. Filter with diatomaceous earth to remove activated charcoal. The water layer is adjusted to pH 3.8 with 2N-hydrochloric acid solution, then left at 5 ° C for 12 hours. The resulting crystals were filtered, washed sequentially with ice water and acetone, and dried to obtain 12.1 g of a white target compound (yield: 80%).
1NMR : (d, DMSO-d6) ; 9.5(d,1H, -CONH-), 9.4(d, 2H, pyridinium 양성자), 8.6(t, 2H, pyridinium 양성자), 8.2(t, 2H, pyridinium 양성자), 7.3(s, 2H, -NH2), 6.7(s, 1H, amino-thiazol 양성자), 5.7(dd, 1H, C7-H), 5.5(ABq, 2H, -CH2-), 5.1(d, 1H, C6-H), 3.3(ABq, 2H, C2-H), 1.4(s, 6H, -C(CH3)2) 1 NMR: (d, DMSO- d 6); 9.5 (d, 1H, -CON H -), 9.4 (d, 2H, pyridinium protons), 8.6 (t, 2H, pyridinium protons), 8.2 (t, 2H, pyridinium protons), 7.3 (s, 2H, -NH 2), 6.7 (s, 1H , amino-thiazol proton), 5.7 (dd, 1H, C 7 -H), 5.5 (ABq, 2H, -CH 2 -), 5.1 (d, 1H, C 6 -H) , 3.3 (ABq, 2H, C 2 -H), 1.4 (s, 6H, -C (CH 3) 2)
미국특허 제5,182,383호의 실시예 1 및 제 4,954,624호의 실시예 2에 따라 종래의 2-아미노 티아졸 카르복실산의 반응성 유도체를 이용하여 세프타지딤 오수화물을 제조하였다.The ceftazidime pentahydrate was prepared using the reactive derivatives of the conventional 2-aminothiazole carboxylic acid according to Example 2 of US Patent No. 5,182,383 and Example 2 of US 4,954,624.
비교예. (6R,7R)-7-{2-(2-아미노티아졸-4-일)-2-(Z)-(2-카르복시프로프-2-옥시이미노)아세트아미도}-3-(1-피리디니움메틸)-세프-3-엠-4-카르복실레이트.펜타하이드레이트(일반명 : 세프타지딤 오수화물)의 제조Comparative Example. (6R, 7R) -7- {2- (2-aminothiazol-4-yl) -2- (Z) - (2-carboxyprop-2- oximino) acetamido} -3- -Pyridiniummethyl) -cep-3-M-4-carboxylate. Preparation of pentahydrate (generic name: ceftazidime pentahydrate)
2-(2-아미노-4-티아졸일)-(Z)-2-[(1-t-부톡시카르보닐-1-메틸에톡시)이미노]티오아세트산-5-벤조티아졸-2-일-에스테르 12g, (6R,7R)-7-아미노-3-(1-피리디니움메틸)-세프-3-엠-4-카르복실레이트모노히드로클로라이드일수화물 7.7g을 디클로로메탄 70mL와 메탄올 5mL의 혼합용액에 현탁시킨 후 트리에틸아민 3.8mL를 가한 후 0℃에서 10시간 동안 교반한다. 생성된 결정을 여과하고 디클로로메탄 소량으로 세척한 후 실온에서 진공 건조한 후 0℃~5℃에서 진한염산 15mL에 가하여 담황록색 용액을 형성한다. 이 용액을 5℃에서 약 1시간 동안 교반한다. 이어 빙수 22.4mL를 가한 후 pH가 4.0~4.1이 될 때까지 고체 중탄산나트륨을 가한다. 온도를 5℃ 이하로 유지한다. 이어서 혼합물을 약 10℃~15℃에서 1~2시간 동안 정치시키고 이에 따라 생성물이 결정화 하기 시작한다. 이어서 3N-염산을 이용하여 pH를 3.6으로 조정하고 혼합물을 0~4℃에서 5시간 동안 추가로 정치시킨다. 이어서 표제 화합물을 분리하고 냉수 및 아세톤으로 세척한 다음 건조시킨다. 이러한 방법에서 표제 화합물 7.73g이 순수한 형태로 수득된다2 - [(1-t-butoxycarbonyl-1-methylethoxy) imino] thioacetic acid-5-benzothiazole- 2- (7R, 7R) -7-amino-3- (1-pyridiniummethyl) -cep-3-m-4-carboxylate monohydrochloride monohydrate (7.7 g) was dissolved in 70 mL of dichloromethane, , And 3.8 ml of triethylamine was added thereto, followed by stirring at 0 ° C for 10 hours. The resulting crystals are filtered, washed with a small amount of dichloromethane, dried in vacuo at room temperature, and then added to 15 mL of concentrated hydrochloric acid at 0 ° C to 5 ° C to form a pale yellow-green solution. This solution is stirred at 5 DEG C for about 1 hour. Add 22.4 mL of ice water and add solid sodium bicarbonate until pH is 4.0 ~ 4.1. Keep the temperature below 5 ° C. The mixture is then allowed to stand at about 10 ° C to 15 ° C for 1 to 2 hours, and the product begins to crystallize. The pH is then adjusted to 3.6 with 3N-hydrochloric acid and the mixture is further allowed to stand at 0? 4 占 폚 for 5 hours. The title compound is then separated, washed with cold water and acetone, and then dried. In this way 7.73 g of the title compound are obtained in pure form
- 수율 : 54.6%- Yield: 54.6%
본 발명은 안정한 결정형 형태로 얻어진 순수한 산할로겐화물을 이용하므로 아실화 반응시 불필요한 불순물이 거의 없어 고순도로 목적화합물을 얻을 수 있을 뿐 아니라, 상기 제조예 및 비교예에서 보는 바와 같이 아실화 반응후 보호기의 제거과정 없이 바로 원하는 목적물을 수득할 수 있어 수율이 높고 훨씬 경제적이다.Since the present invention uses a pure acid halide obtained in a stable crystalline form, there is no unnecessary impurity in the acylation reaction and the target compound can be obtained with high purity. In addition, as shown in the preparation examples and the comparative examples, The desired product can be obtained directly without the removal process of the catalyst, resulting in high yield and economical efficiency.
이상 설명하고 실시예를 통하여 알 수 있는 바와 같이, 본 발명의 화합물은 3-세펨 화합물의 아미노기와 아실화반응 전에 각각의 보호기가 제거된 순수한 결정형 형태의 산할로겐화물로 얻어지고, 이를 이용하여 세프타지딤, 세픽심 등을 제조할 때 아실화 반응 후 부산물들이 거의 없는 세펨계 목적화합물을 제조할 수 있는 효과가 있다.As can be seen from the foregoing description, the compound of the present invention is obtained as an acid halide in pure crystalline form in which each protecting group is removed before the acylation reaction with the amino group of the 3-cephem compound, Tareddim, and cetearmium, it is possible to produce a target compound of CeFeY, which has almost no by-products after the acylation reaction.
Claims (8)
Priority Applications (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020000011127A KR100342600B1 (en) | 2000-03-06 | 2000-03-06 | New Thiazole compounds and their preparations |
| US09/564,979 US6277996B1 (en) | 2000-03-06 | 2000-05-04 | Thiazole compound and a process thereof |
| DE60143841T DE60143841D1 (en) | 2000-03-06 | 2001-03-06 | NEW THIAZOL COMPOUNDS AND METHOD FOR THE PRODUCTION THEREOF |
| EP01912526A EP1274695B1 (en) | 2000-03-06 | 2001-03-06 | New thiazol compounds and their preparations |
| PCT/KR2001/000333 WO2001066532A1 (en) | 2000-03-06 | 2001-03-06 | New thiazol compounds and their preparations |
| JP2001565348A JP4022070B2 (en) | 2000-03-06 | 2001-03-06 | Novel thiazole compound and method for producing the same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020000011127A KR100342600B1 (en) | 2000-03-06 | 2000-03-06 | New Thiazole compounds and their preparations |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| KR20010087055A KR20010087055A (en) | 2001-09-15 |
| KR100342600B1 true KR100342600B1 (en) | 2002-07-04 |
Family
ID=19652652
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020000011127A KR100342600B1 (en) | 2000-03-06 | 2000-03-06 | New Thiazole compounds and their preparations |
Country Status (6)
| Country | Link |
|---|---|
| US (1) | US6277996B1 (en) |
| EP (1) | EP1274695B1 (en) |
| JP (1) | JP4022070B2 (en) |
| KR (1) | KR100342600B1 (en) |
| DE (1) | DE60143841D1 (en) |
| WO (1) | WO2001066532A1 (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100342600B1 (en) * | 2000-03-06 | 2002-07-04 | 한미정밀화학주식회사 | New Thiazole compounds and their preparations |
| KR100392409B1 (en) * | 2000-03-20 | 2003-07-22 | 한미정밀화학주식회사 | A process for preparing cephalosporine derivatives using new thiazole compound |
| JP2004149412A (en) * | 2000-06-21 | 2004-05-27 | Fujisawa Pharmaceut Co Ltd | Method for producing 7-[2-(2-aminothiazol-4-yl)-2-lower alkoxycarbonylmethoxyiminoacetamido]-3-cephem compound |
| CN1312158C (en) * | 2005-05-20 | 2007-04-25 | 天津市医药集团技术发展有限公司 | Method for preparing cefixime |
| CN102199132A (en) * | 2011-03-02 | 2011-09-28 | 河北科技大学 | Method for preparing 2-(2-amino-4-thiazole)-2(Z)-[[(tertbutyloxycarbonyl) methoxyl] imido] acetic acid and salt thereof |
| CN102924483B (en) * | 2012-10-31 | 2015-06-17 | 海南合瑞制药股份有限公司 | Ceftazidime crystal compound, preparation method of compound and pharmaceutical composition of compound in sterile mixed powder form |
| CN103044415A (en) * | 2012-12-17 | 2013-04-17 | 浙江华方药业有限责任公司 | Synthesis method for aztreonam |
| CN103044416A (en) * | 2012-12-17 | 2013-04-17 | 浙江华方药业有限责任公司 | Synthetic method of Carumonam sodium |
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| JPS60208986A (en) * | 1984-03-31 | 1985-10-21 | Toyama Chem Co Ltd | Novel cephalosporin |
| JPH02790A (en) * | 1988-01-07 | 1990-01-05 | Fujisawa Pharmaceut Co Ltd | Production of 7-(2-(2-aminothiazol-4yl)-2-hydroxyiminoacetamide)-3-cephem compound |
| EP0475150A1 (en) * | 1990-08-23 | 1992-03-18 | Bristol-Myers Squibb Company | Antibiotic C-3 di-hydroxyphenyl substituted cephalosporin compounds, compositions and use thereof |
| KR950013571A (en) * | 1993-11-18 | 1995-06-15 | 미첼 보스케트 | Mechanisms and cohesive or liquid mixed conduit installations and use of such mechanisms |
| WO2001066532A1 (en) * | 2000-03-06 | 2001-09-13 | Hanmi Fine Chemicals Co., Ltd. | New thiazol compounds and their preparations |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AR228726A1 (en) | 1978-05-26 | 1983-04-15 | Glaxo Group Ltd | PROCEDURE FOR THE PREPARATION OF ANTIBIOTIC (6R, 7R) -7 - ((Z) -2- (2-AMINOTIAZOL-4-IL) -2- (2-CARBOXIPROP-2-OXIIMINO) ACETAMIDO) -3- (1- PIRIDINIOMETIL) CEF-3-EM-4-CARBOXILATO |
| JPS5612397A (en) | 1979-05-25 | 1981-02-06 | Glaxo Group Ltd | Intermediate for manufacture of cephalosporin antibiotic |
| FR2494275A2 (en) * | 1980-11-20 | 1982-05-21 | Rhone Poulenc Ind | NEW DERIVATIVES OF VINYL-3 CEPHALOSPORINS AND THEIR PREPARATION |
| EP0101148B1 (en) * | 1982-04-29 | 1987-12-23 | Glaxo Group Limited | Thiazole derivative, process for its preparation and use in the preparation of beta-lactam antibiotics |
| US5182383A (en) | 1986-09-10 | 1993-01-26 | Biochemie Gesellschaft M.B.H. | Stable, crystalline form of a cephalosporin intermediate product |
| DD279887A1 (en) * | 1987-07-03 | 1990-06-20 | Inst Pharmakologische Forschun | METHOD OF PREPARING D-ALPHA- (4 (1H) -1,5-NAPHTHYRIDONE-3-CARBOXAMIDO) -BENZYLPENICILLIN AND OTHER BETA LACTAMANTIBIOTICS |
| JPH0635464B2 (en) * | 1988-09-02 | 1994-05-11 | 明治製菓株式会社 | Novel cephem compound, its production method and antibacterial agent |
| TW538045B (en) | 1997-01-16 | 2003-06-21 | Biochemie Gmbh | Process for purifying cefixime |
-
2000
- 2000-03-06 KR KR1020000011127A patent/KR100342600B1/en not_active IP Right Cessation
- 2000-05-04 US US09/564,979 patent/US6277996B1/en not_active Expired - Lifetime
-
2001
- 2001-03-06 JP JP2001565348A patent/JP4022070B2/en not_active Expired - Lifetime
- 2001-03-06 EP EP01912526A patent/EP1274695B1/en not_active Expired - Lifetime
- 2001-03-06 DE DE60143841T patent/DE60143841D1/en not_active Expired - Lifetime
- 2001-03-06 WO PCT/KR2001/000333 patent/WO2001066532A1/en active Application Filing
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE279887C (en) * | ||||
| JPS60208986A (en) * | 1984-03-31 | 1985-10-21 | Toyama Chem Co Ltd | Novel cephalosporin |
| JPH02790A (en) * | 1988-01-07 | 1990-01-05 | Fujisawa Pharmaceut Co Ltd | Production of 7-(2-(2-aminothiazol-4yl)-2-hydroxyiminoacetamide)-3-cephem compound |
| EP0475150A1 (en) * | 1990-08-23 | 1992-03-18 | Bristol-Myers Squibb Company | Antibiotic C-3 di-hydroxyphenyl substituted cephalosporin compounds, compositions and use thereof |
| KR950013571A (en) * | 1993-11-18 | 1995-06-15 | 미첼 보스케트 | Mechanisms and cohesive or liquid mixed conduit installations and use of such mechanisms |
| WO2001066532A1 (en) * | 2000-03-06 | 2001-09-13 | Hanmi Fine Chemicals Co., Ltd. | New thiazol compounds and their preparations |
Also Published As
| Publication number | Publication date |
|---|---|
| JP4022070B2 (en) | 2007-12-12 |
| EP1274695B1 (en) | 2011-01-12 |
| KR20010087055A (en) | 2001-09-15 |
| DE60143841D1 (en) | 2011-02-24 |
| EP1274695A1 (en) | 2003-01-15 |
| EP1274695A4 (en) | 2004-09-15 |
| JP2003525932A (en) | 2003-09-02 |
| US6277996B1 (en) | 2001-08-21 |
| WO2001066532A1 (en) | 2001-09-13 |
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